CN1195349A - Cyclic GMP-specific phosphodiesterase inhibitors - Google Patents

Cyclic GMP-specific phosphodiesterase inhibitors Download PDF

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CN1195349A
CN1195349A CN96196751A CN96196751A CN1195349A CN 1195349 A CN1195349 A CN 1195349A CN 96196751 A CN96196751 A CN 96196751A CN 96196751 A CN96196751 A CN 96196751A CN 1195349 A CN1195349 A CN 1195349A
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hydrogen
benzofuryl
pyrido
indoles
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CN1069318C (en
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A·C·M·道干
F·格利堡特
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Abstract

A compound of formula (I) and solvates thereof, in which R<0> represents hydrogen, halogen or C1-6alkyl; R<1> represents hydrogen or C1-6alkyl; R<2> represents the bicyclic ring (1) which may be optionally substituted by one or more groups selected from halogen and C1-3alkyl; and R<3> represents hydrogen or C1-3alkyl. A compound of the present invention is a potent and selective inhibitor of cGMP specific PDE having a utility in a variety of therapeutic areas where such inhibition is beneficial.

Description

Cyclic GMP-specific phosphodiesterase inhibitors
The present invention relates to a series of tetracyclics, their preparation method contain their pharmaceutical composition, and they is as the application of therapeutical agent.More specifically say, the present invention relates to tetracyclic, they be cyclic guanosine 3 ', the strong effective selectivity inhibitor of 5 ＇-phosplate specific phosphodiesterase enzyme (cGMP specific PDE), various treatments field useful to this inhibition comprises the treatment of cardiovascular disorder, has effectiveness.
Therefore, a first aspect of the present invention has provided formula I compound and solvate (as hydrate) thereof:
Figure A9619675100041
Wherein: R 0Represent hydrogen, halogen or C 1-6Alkyl; R 1Represent hydrogen or C 1-6Alkyl; R 2Represent bicyclic ring
This ring can be randomly by one or more halogen and C of being selected from 1-3The group of alkyl replaces;
With
R 3Represent hydrogen or C 1-3Alkyl.
Terminology used here " halogen " is meant bromine, chlorine, fluorine and iodine.
Terminology used here " C 1-3Alkyl " and " C 1-6Alkyl " be meant the straight or branched alkyl, as methyl, ethyl, sec.-propyl, normal-butyl, amyl group, hexyl etc.
Particularly preferred group's The compounds of this invention is R wherein 0Represent the compound of hydrogen.
Further preferred group's The compounds of this invention is R wherein 1Be selected from hydrogen, the compound of methyl and sec.-propyl.
Preferred R 2Represent unsubstituted bicyclic ring:
Further preferred group's formula (I) compound is R wherein 3Represent the compound of hydrogen or methyl.
Should be appreciated that the appropriate combination that the present invention includes all above-mentioned particularly preferred and preferred groups.
Formula (I) compound can contain one or more asymmetric centers, thereby can exist with enantiomorph or diastereomeric form.Should be appreciated that the mixture and the isolating individual isomer of these two kinds of forms of the formula of the present invention includes (I) compound.Preferred especially 6R and 12aR isomer.
Particularly preferred simplification compound of the present invention comprises: (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-6-(5-benzofuryl)-2-methyl-pyrazine is [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1 also, the 4-diketone; (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-6-(5-benzofuryl)-pyrazine is [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1 also, the 4-diketone; (12aR)-2,3,6,7,12,12a-six hydrogen-6-(5-benzofuryl)-3-methyl-pyrazine is [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1 also, the 4-diketone for 3S, 6R; (12aR)-2,3,6,7,12,12a-six hydrogen-6-(5-benzofuryl)-2,3-dimethyl-pyrazine are [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1 also, the 4-diketone for 3S, 6R; (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-6-(5-benzofuryl)-2-sec.-propyl-pyrazine is [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1 also, the 4-diketone; And the physiologically acceptable solvate (as hydrate) of above-claimed cpd.
The most special The compounds of this invention be (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-6-(5-benzofuryl)-2-methyl-pyrazine also [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1,4-diketone and physiologically acceptable solvate (as hydrate) thereof.
Proved already that The compounds of this invention was the strong effective selectivity inhibitor of cGMP specific PDE.Therefore, formula (I) compound is applicable to the treatment use, especially for the treatment that wherein inhibition of cGMP specific PDE is had the various disease conditions of useful value.
Because it is active that the selectivity PDE5 that The compounds of this invention showed suppresses, make the cGMP level increase, produce favourable antiplatelet, anti-neutrophil, vasospasm, vasorelaxation so again, short natruresis and diuretic activity, and enhancing endothelium derivation relaxation factor (EDRF), nitro vasodilator (nitrovasodilators), atrial natriuretic peptide (ANF), B-Type natriuretic peptide (BNP), C type natriuretic peptide (CNP) and endothelium dependent form relaxant such as bradykinin, vagusstoff and 5-HT 1Effect.Therefore, formula (I) compound has effectiveness aspect the treatment of various disease conditions, these illnesss comprise stable form, instability mode and anomaly (Prinzmetal) stenocardia, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, the illness (as the illness after the percutaneous transluminal coronary angioplasty) of minimizing blood vessel patent, the periphery vascular disease, vascular disease such as Raynaud disease, diseases associated with inflammation, apoplexy, bronchitis, chronic asthma, atopic asthma, rhinallergosis, glaucoma, erectile dysfunction and be the disease (as the big bowel syndrome of supersensitivity) of feature with the intestinal motility obstacle.
Be understood that treatment described here comprises the illness that prevention and treatment are determined.
Equally, be understood that, the form that ' formula (I) compound ' or its physiologically acceptable salt or solvate can compounds itself, or use with the pharmaceutical compositions that includes any above-claimed cpd.
Therefore, formula (I) compound that is used for the treatment of following illness that provided on the one hand more of the present invention: stable form, instability mode and anomaly (Prinzmetal) stenocardia, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, the illness (as the illness behind the PTCA) of minimizing blood vessel patent, the periphery vascular disease, vascular disease such as Raynaud disease, diseases associated with inflammation, apoplexy, bronchitis, chronic asthma, atopic asthma, rhinallergosis, glaucoma, erectile dysfunction or be the disease (as IBS) of feature with the intestinal motility obstacle.
Another aspect of the present invention has provided the application of formula (I) compound in the medicine of the following illness of preparation treatment: stable form, instability mode and anomaly (Prinzmetal) stenocardia, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, reduce the illness (as the illness behind the PTCA) of blood vessel patent, periphery vascular disease, vascular disease such as Raynaud disease, diseases associated with inflammation, apoplexy, bronchitis, chronic asthma, atopic asthma, rhinallergosis, glaucoma, erectile dysfunction or be the disease (as IBS) of feature with the intestinal motility obstacle.
Another aspect of the present invention has provided the method for the following illness of the treatment mankind or non-human animal's body: stable form, instability mode and anomaly (Prinzmetal) stenocardia, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, the illness (as the illness behind the PTCA) of minimizing blood vessel patent, periphery vascular disease, vascular disease such as Raynaud disease, diseases associated with inflammation, apoplexy, bronchitis, chronic asthma, atopic asthma, rhinallergosis, glaucoma, erectile dysfunction or be the disease (as IBS) of feature with the intestinal motility obstacle, this method comprises uses significant quantity formula (I) compound to described people or non-human animal's body.
The compounds of this invention can be used by any suitable pathways, for example, by per os, through cheek, the hypogloeeis, rectum, vagina, intranasal, local or non-enteron aisle (comprising intravenously, in the intramuscular, subcutaneous and hat) uses by approach.Usually preferred oral is used.
For the medication of being used for the treatment of property or the human above-mentioned illness of prophylactic treatment, the oral dosage of formula (I) compound is generally every 70kg mean body weight adult patient 0.5-800mg every day.Therefore, for typical adult patient, contain 0.2-400mg in single tablet or the capsule and be blended in activeconstituents in pharmaceutically acceptable vehicle or the carrier, they can single dose or multiple doses use, use one or many every day.If necessary, intravenously, be generally every single dose 0.1-400mg through the dosage of cheek or sublingual administration.In fact, the actual therapeutic regimen of suitable individual patient is determined by the doctor in charge, and with age of particular patient, body weight and reaction and change.Above-mentioned dosage be under the average situation typical doses, but may exist needs higher or than the individual situation of low dosage scope, all these are all within the scope of the invention.
Use for the mankind, formula (I) compound can be used separately, but normally to use with the pharmaceutical carrier institute blended form of predetermined route of administration of basis and standard drug choice of practice.For example, compound can be oral with following dosage form, through cheek or sublingual administration: contain the tablet of vehicle such as starch or lactose, or inclusion compound itself or also be mixed with the capsule or the ovulum of vehicle only, or contain the elixir or the suspension of seasonings or tinting material.These liquid preparations can be with pharmaceutically useful additive such as suspension agent (as methylcellulose gum, the mixture of the mixture of semi-synthetic glyceryl ester such as witepsol or glyceride mixture such as Prunus amygdalus oil and PEG-6 ester or PEG-8 and caprylic/last of the ten Heavenly stems ester) preparation.Compound can also pass through non-enteron aisle such as intravenously, intramuscular, subcutaneous or hat inner injecting and administering.For parenterai administration, compound is preferably used with the aseptic aqueous solution form, can contain other material in this aseptic aqueous solution, and for example salt, or monose such as mannitol or glucose are so that solution and blood isoosmotic pressure.
Therefore, one side more of the present invention has provided pharmaceutical composition, comprising formula (I) compound and acceptable diluents or carrier.
Another aspect of the present invention has provided the method for preparing the pharmaceutical composition that comprises formula (I) compound, and this method comprises together mixes formula (I) compound with acceptable diluents or carrier.
Formula (I) compound also can be used in combination with other therapeutical agent that can be used for treating above-mentioned morbid state.Therefore another aspect of the present invention has provided the binding substances of formula (I) compound and other active therapeutic agent.
Above-mentioned binding substances can be easily uses with pharmaceutical dosage forms, and the pharmaceutical composition that therefore comprises binding substances as mentioned above and pharmaceutically acceptable diluent or carrier has further constituted another aspect of the present invention.
Every kind of component of this binding substances can also or be used simultaneously with isolating pharmaceutical dosage forms order.
The appropriate formulation that is used for combining with formula (I) compound the known treatment agent of medication will be apparent to those skilled in the art.
Formula (I) compound can perhaps prepare with following method with any appropriate method preparation as known in the art, and they have constituted another part of the present invention.In following method, except as otherwise noted, R 0, R 1, R 2And R 3The same following formula of definition (I) described in.
For example, first method (A) of preparation formula (I) compound is included in suitable solvent as in alcohol (as methyl alcohol or ethanol) or the solvent mixture, uses primary amine R at 20 ℃ to reflux temperature (50 ℃ according to appointment) easily 1NH 2Processing formula (II) mixture: (wherein Alk represents C 1-C 6Alkyl, as methyl or ethyl, and Hal represents halogen atom, as chlorine).
Second method (B) of preparation formula (I) compound is included in catalyzer (as palladium-gac) and exists down, suitable solvent as alcohol (as methyl alcohol or ethanol) in, hydrogenation of formula (III) compound at elevated temperatures: Wherein: the definition of Alk is the same, and Cbz represents carbobenzoxy-(Cbz).
Formula (II) compound can prepare easily by following method: at suitable solvent such as halohydrocarbon (as trichloromethane or methylene dichloride), or in the ether (as tetra oxygen furyl), preferably at alkali such as organic amine (as trialkylamine such as triethylamine) or alkaline carbonate or supercarbonate (as NaHCO 3) exist down, use halo acetyl halide (as chloroacetyl chloride) processing formula (IV) compound:
Figure A9619675100091
This reaction can (under 0 ℃) be carried out under-20 ℃ to+20 ℃ easily.Formula (IV) compound can be prepared easily by formula V tryptophane alkyl ester:
This step comprises formula V compound and aldehyde R 2Pictet-Spengler ring-closure reaction between CHO.Reaction can be carried out in suitable solvent such as halohydrocarbon (as methylene dichloride) or aromatic hydrocarbons (as toluene) in the presence of acid (as trifluoroacetic acid) easily.This reaction can be carried out to reflux temperature easily at-20 ℃, step production (III) compound.Reaction also can be carried out under reflux conditions in solvent such as aromatic hydrocarbons (as benzene or toluene), wherein the water that randomly uses Dean and Stark apparatus to be generated to tell.Reaction produces cis and trans-isomer(ide) mixture, is racemize or enantiomer-pure tryptophane alkyl ester according to used initial substance, and these isomer can be single enantiomers or be cis or the right racemic modification of trans-isomer(ide).Adopt fractionation crystallization or use suitable solvent to make the chromatography (as flash column chromatography) of eluent, can from its mixture, isolate single cis or trans enantiomer easily.Similarly, adopt to use the chromatography (as flash column chromatography) of suitable eluent to separate cis and trans-isomer(ide) is right.Utilize suitable epimerization method, optically pure trans-isomer(ide) can also be changed into the pure cis-isomeride of optically-active.A kind of in these class methods is included in 0 ℃ to the reflux temperature of solution, handles the mixture (as 1: 1 mixture) of trans-isomer(ide) or cis and trans-isomer(ide) with methanolizing or hydration hydrogenchloride.Chromatography (as rapid column chromatography) mixture separates the diastereomer that is produced then.
Formula (III) compound can be by making aforesaid formula (IV) and formula (VI) compound prepared in reaction:
Figure A9619675100093
Wherein the definition of Cbz as above.Reaction suits 1, and 3-dicyclohexylcarbodiimide (DCC) exists down, in solvent such as halohydrocarbon (as methylene dichloride), carries out to room temperature in 0 ℃.
Formula V and (VI) compound be known compound, perhaps available standard method preparation hereinafter described.
By with suitable solvent crystallization or evaporate suitable solvent, The compounds of this invention can separate with the mutually associating mode of solvent molecule and obtains.
Therefore, the method (C) that has provided preparation formula (I) compound or its solvate (as hydrate) more on the one hand of the present invention, this method comprises aforesaid method (A) or (B), that continues also comprises:
I) mutual step of converting; And/or
Ii) solvate (as hydrate) forms step.
The following non-limiting example of synthetic usefulness of The compounds of this invention and intermediate thereof is illustrated.Intermediate 1 and 2 (1R, 3R)-1,2,3,4-tetrahydrochysene-1-(5-benzofuryl)-9H-pyrido [3,4-b] indole-3-carboxylic acid methyl ester, cis-isomeride and (1S, 3R)-1,2,3,4-tetrahydrochysene-1-(5-benzofuryl)-9H-pyrido [3,4-b] indole-3-carboxylic acid methyl ester's trans-isomer(ide)
To the D-tryptophan methyl ester (3.73g) and the 5-formyl benzofuran that are cooled to 0 ℃ 1Be added dropwise to trifluoroacetic acid (2.63ml) in anhydrous methylene chloride (2.5g) (100ml) stirred solution, solution is at room temperature reacted.After 72 hours, solution washs successively with saturated aqueous solution of sodium bicarbonate and water, and uses dried over sodium sulfate.The reduction vaporization organic layer, residue passes through purified by flash chromatography, with dichloromethane/ethyl acetate (90/10) wash-out, obtain cis-isomeride (intermediate 1) earlier (3g), be the amorphism compound, then obtain trans-isomer(ide) (intermediate 2) and (2.5g), be white crystals, m.p.:194-195 ℃.
15-formyl benzofuran synthetic sees Chimie Therapeutique 4, described in the pp 221-227 (1966).Intermediate 3 (1R, 3R)-1,2,3,4-tetrahydrochysene-1-(5-benzofuryl)-2-chloracetyl-9H-pyrido [3,4-b] indole-3-carboxylic acid methyl ester
In anhydrous methylene chloride (40ml) stirred solution that is cooled to 0 ℃ intermediate 1 (2g) and triethylamine (0.88ml), be added dropwise to chloroacetyl chloride (0.5ml), and solution was stirred 1 hour under same temperature.Wash solution subsequently with water, with dried over sodium sulfate and be evaporated to driedly, the residue recrystallizing methanol obtains title compound (1.8g), is light yellow crystallization.
m.p.：227-228℃。Intermediate 4 (1R.3R)-1,2,3,4-tetrahydrochysene-1-(5-benzofuryl)-2-(2-(S)-benzyloxycarbonyl amino propionyl)-9H-pyrido [3,4-b] indole-3-carboxylic acid methyl ester
Under 0 ℃, to (the S)-2-benzyloxycarbonyl amino propionic acid (1.3g) and 1 that is stirring, 3-dicyclohexyl carbodiimide (DCC) (1.2g) adds intermediate 1 (1.0g) in the solution in anhydrous methylene chloride (50ml).Stir formed mixture 72 hours, and leached the precipitation that is produced then.Evaporated filtrate is to doing, and residue with cyclohexane/ethyl acetate (60/40) wash-out, obtains white crystals title compound (1.4g), m.p.:91-92 ℃ by purified by flash chromatography.Intermediate 5 (1R, 3R)-1,2,3,4-tetrahydrochysene-1-(5-benzofuryl)-2-[2-(S)-carbobenzoxy-(Cbz) methylamino) propionyl]-9H-pyrido [3,4-b] indole-3-carboxylic acid methyl ester
Adopt the method identical with the preparation of intermediate 4, but with 2-(S)-carbobenzoxy-(Cbz) methylamino) propionic acid (0.82g) is raw material, and use intermediate 1 (0.6g), DCC (0.72g) and methylene dichloride (25ml), behind the chromatography [using cyclohexane/ethyl acetate (70/30) to be eluent], obtain title compound, be the white foam body. 1H NMR (240MHz, CDCl 3) δ 7.7 (s, 1H), 7.6 (d, 2H), 7.4-7.05 (m, 11H), 6.6 (d, 1H), 5.4-5.0 (m, 4H), 3.5 (d, 1H), 3.0 (m, 1H), 2.9-2.7 (m, 6H), 2.6 (dd, 1H), 1.3 (s, 3H). embodiment 1 (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-6-(5-benzofuryl)-2-methylpyrazine is [2 ', 1 ': 6,1] pyrido [3,4-b] indoles 1,4-diketone also
Under the room temperature, in methyl alcohol (30ml) suspension of the intermediate 3 (0.42g) that is stirring, add methylamine solution (33% ethanolic soln) (0.47ml), and under nitrogen atmosphere, formed mixture was heated 72 hours down at 50 ℃.Removal of solvent under reduced pressure, and residue is dissolved in methylene dichloride.After washing, dried over sodium sulfate and being evaporated to were done, crude product was purified with methanol crystallization, obtains white crystals title compound (0.21g).M.p.:291-293 ℃. ultimate analysis C 23H 19N 3O 3: calculated value: C, 71.68; H, 4.97; N, 10.90; Measured value: C, 71.5; H, 4.91; N, 10.74%.[α] 20 D=+55.7 ° of (C=1; CHCl 3).
Following compound makes in a similar manner: embodiment 2 (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-6-(5-benzofuryl)-pyrazine be [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1 also, the 4-diketone
Adopt the method identical, but be raw material, after with recrystallizing methanol, obtain the white crystals title compound with ammonia and intermediate 3 with the preparation of embodiment 1.M.p.:310-311 ℃. ultimate analysis C 22H 17N 3O 3(0.4MeOH): calculated value: C, 70.03; H, 4.88; N, 10.94; Measured value: C, 70.01; H, 4.8; N, 10.61%.[α] 20 D=+60.4 ° of (C=0.5; Pyridine). (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-6-(5-benzofuryl)-2-sec.-propyl-pyrazine is [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1 also, the 4-diketone for embodiment 3
Adopt the method identical, but be raw material, after with recrystallizing methanol, obtain the white crystals title compound with Isopropylamine and intermediate 3 with the preparation of embodiment 1.M.p.:291-292 ℃. ultimate analysis C 25H 23N 3O 3(0.6MeOH): calculated value: C, 71.06; H, 5.92; N, 9.71; Measured value: C, 70.94; H, 5.62; N, 9.77%.[α] 20 D=+37.9 ° of (C=1; CHCl 3). (12aR)-2,3,6,7,12,12a-six hydrogen-6-(5-benzofuryl)-3-methyl-pyrazine is [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1 also, the 4-diketone for 3S, 6R for embodiment 4
In the presence of 10%Pd/C (30mg), methyl alcohol (10ml) solution of intermediate 4 (0.3g) was stirred 2 hours in 50 ℃ under nitrogen atmosphere.Reaction mixture, by diatomite filtration, filter cake is with methanol wash and vacuum-evaporation filtrate.The residue purified by flash chromatography uses methylene chloride (98/2) to be eluent, after with recrystallizing methanol, obtains white crystals title compound (0.15g).M.p.:150-151 ℃. ultimate analysis C 23H 19N 3O 3(0.1MeOH): calculated value: C, 71.39; H, 5.03; N, 10.81; Measured value: C, 71.08; H, 5.16; N, 10.50%.[α] 20 D=+50 ° of (C=0.25; CHCl 3). (12aR)-2,3,6,7,12,12a-six hydrogen-6-(5-benzofuryl)-2,3-dimethyl-pyrazine are [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1 also, the 4-diketone for 3S, 6R for embodiment 5
Adopt the method identical, but be raw material and use 10%Pd/C (50mg) in methyl alcohol (20ml), to carry out, after with recrystallizing methanol, obtain white crystals title compound (40mg) with intermediate 5 (0.52g) with the preparation of embodiment 4.M.p.:323-324 ℃. ultimate analysis C 24H 21N 3O 3(0.1MeOH): calculated value: C, 71.52; H, 5.35; N, 10.43; Measured value: C, 71.71; H, 5.44; N, 10.39%.[α] 20 D=+53 ° of (C=0.35; CHCl 3). tablet A. straight pressing for oral use
????1. The mg/ sheet
Activeconstituents Crospovidone USNF Magnesium Stearate European Pharmacopoeia lactose hydrous ????50.0 ????8.0 ????1.0 ????141.0
Activeconstituents sieved and with the vehicle fusion.Compacting gained mixture is pressed and is formed tablet.
2. The mg/ sheet
Activeconstituents colloid silica Crospovidone sodium lauryl sulphate Magnesium Stearate European Pharmacopoeia Microcrystalline Cellulose USNF ????50.0 ????0.5 ????8.0 ????1.0 ????1.0 ????139.5
The screening activeconstituents and with the vehicle fusion.Compacting gained mixture becomes tablet.B. wet granulation method
????1. The mg/ sheet
Active component polyvinylpyrrolidone polyethylene glycol Tween 80 dolomol European Pharmacopoeia cross-linked carboxymethyl cellulose is received cataloid microcrystalline cellulose USNF ????50.0 ????150.0 ????50.0 ????10.0 ????2.5 ????25.0 ????2.5 ????210.0
With polyvinylpyrrolidone, polyoxyethylene glycol and tween 80 are soluble in water.Gained solution is used for and activeconstituents granulating together.After the drying, the screening particle pushes under High Temperature High Pressure then.Mill then and/or sieve extrudate, with Microcrystalline Cellulose, cross-linked carboxymethyl cellulose is received again, colloid silica and Magnesium Stearate fusion.Compacting gained mixture forms tablet.
????2. The mg/ sheet
Activeconstituents tween 80 lactose European Pharmacopoeia starch BP pre-gelled W-Gum BP Magnesium Stearate BP ????50.0 ????3.0 ????178.0 ????45.0 ????22.5 ????1.5
Screening activeconstituents and and lactose, starch and the together fusion of pre-gelled W-Gum.Tween 80 is dissolved in purifies waste water.Add proper volume amount tween 80 solution, with the meal granulating.After the drying, the screening particle and with the Magnesium Stearate fusion.Compressed granulate forms tablet then.
The tablet of other intensity can be by changing the amount ratio preparation of activeconstituents and other vehicle.Coated tablet
The above-mentioned tablet of dressing.
Dressing suspension ?????％W/W
Opadryl white-1 pure water Ph Eur 13.2 to 100.0 *
*Anhydrous existence in the final product.Used solid theoretical maximum weight is the 20mg/ sheet in the dressing process.
+ Opadry white system is from Colorcon Limited, and the patented product that UK obtains wherein comprises Vltra tears, titanium dioxide and Vanay.
Use conventional dressing machine, with dressing suspension coated tablet.Capsule
????1. The mg/ capsule
Activeconstituents lactose polyvinylpyrrolidone Magnesium Stearate ????50.0 ????148.5 ????100.0 ????1.5
The screening activeconstituents and with the vehicle fusion.Adopt appropriate device, mixture is filled in No. 1 hard gelatin capsule.
????2. The mg/ capsule
Activeconstituents Microcrystalline Cellulose sodium lauryl sulphate Crospovidone Magnesium Stearate ????50.0 ????233.5 ????3.0 ????12.0 ????1.5
The screening activeconstituents and with the vehicle fusion.Adopt appropriate device, mixture is filled in No. 1 gelatine capsule.
Other preparation can be by changing the ratio of activeconstituents and vehicle, filler weight and change the capsule size if necessary and prepare.
????3. The mg/ capsule
Activeconstituents Labrafil M1944CS 50.0 to 1.0ml
The screening activeconstituents and with the Labrafil fusion.Use appropriate device, suspensoid is filled in the soft gel capsule.Restraining effect to cGMP-PDE
The people's such as Wells of the active employing improvement of the cGMP-PDE of The compounds of this invention one go on foot assay method (Wells, J.N., Baird, C.E., Wu, Y.J. and Hardman, J.G., biological chemistry and Acta Biophysica Sinica (Biochim.Biophys.Acta) 384,430 (1975)) measure.Contain 50mM Tris-HCl in the reaction medium, pH7.5,5mM magnesium acetate, 250 μ g/ml5 ＇-phosphonucleases, 1mM EGTA and 0.15 μ M8-[H 3]-cGMP.Used enzyme behaviour reorganization PDE V (ICOS, Seattle USA).
The compounds of this invention is dissolved in DMSO, and measuring the ultimate density of using is 2%.The incubation time is 30 minutes, during the total conversion rate of substrate be no more than 30%.
According to concentration-response curve (using the typical concentration of 10nM-10 μ M), measure the IC of test-compound 50Value.The test that resists other PDE enzyme that utilizes standard method to carry out shows also that also The compounds of this invention has highly selective to cGMP specific PDE enzyme.The cGMP level determination
In 24 hole culture dish, use the 10-25 be paved with the rat aorta smooth muscle cell (RSMC) [cell is pressed people such as Chamley at cell tissue research (Cell TissueRes.), 177, the method described in the 503-522 (1977) makes] that goes down to posterity.The sucking-off nutrient solution is with PBS (0.5ml) displacement of the test-compound that contains suitable concn.After 30 minutes, adding ANF (100nM) stimulated uridylic acid cyclase particle 10 minutes at 37 ℃ of incubations.When incubation finishes, shift out nutrient solution, add 65% ethanol (0.25ml) and extract twice.Compile ethanol extract twice, adopt the Speed-vac system to be evaporated to dried.After the acetylize, measure c-GMP by scintillation proximity assay (AMERSHAM).EC 50Value is represented to produce half the required dosage that stimulates under the saturation concentration.
Biological data
Find that The compounds of this invention generally demonstrates the IC that is lower than 500nM 50Value and be lower than the EC of 5 μ M 50Value.The in vitro tests data of representative compounds of the present invention are shown in the following table.
Table 1. in vitro tests result
The embodiment numbering ???IC 50nM ???EC 50μM
????????1 ?????15 ????0.6
????????2 ?????20 ????＜1
????????3 ?????30 ????＜1
????????4 ?????8 ????＜1
????????5 ?????8 ????＜1
The clear-headed essential hypertension rat (SHR of the ypotension effect of the The compounds of this invention shown in the table 2 s) research.Oral giving with 5mg/kg dosage compound (being dissolved in 5%DMF and the 95% mixed with olive oil thing).The conduit that is inserted in the carotid artery is measured blood pressure, and continuous recording is 5 hours after the administration.The result is with blood pressure reduction value and time relation area under a curve (0-5 hour AUC, mmHg. hour) expression.Table 2. in vivo test result
The embodiment numbering ????AUCPO(mmHg.h)
???????1 ?????????137
???????2 ??????????93
???????3 ?????????108
???????4 ?????????101
???????5 ??????????89

Claims (13)

1. formula (I) compound and solvate thereof:
Figure A9619675100021
Wherein: R 0Represent hydrogen, halogen or C 1-6Alkyl; R 1Represent hydrogen or C 1-6Alkyl; R 2Represent bicyclic ring
Figure A9619675100022
This ring can be randomly by one or more halogen and C of being selected from 1-3The group of alkyl replaces; And R 3Represent hydrogen or C 1-3Alkyl.
2. according to the compound of claim 1, R wherein 0Represent hydrogen.
3. according to the compound of claim 1 or 2, R wherein 1Be selected from hydrogen, methyl and sec.-propyl.
4. according to each compound among the claim 1-3, wherein R 3Represent hydrogen or methyl.
5. (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-6-(5-benzofuryl)-2-methyl-pyrazine is [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1 also, the 4-diketone; (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-6-(5-benzofuryl)-pyrazine is [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1 also, the 4-diketone; (12aR)-2,3,6,7,12,12a-six hydrogen-6-(5-benzofuryl)-3-methyl-pyrazine is [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1 also, the 4-diketone for 3S, 6R; (12aR)-2,3,6,7,12,12a-six hydrogen-6-(5-benzofuryl)-2,3-dimethyl-pyrazine are [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1 also, the 4-diketone for 3S, 6R; (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-6-(5-benzofuryl)-2-sec.-propyl-pyrazine is [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1 also, the 4-diketone; And their physiologically acceptable solvate.
6. (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-6-(5-benzofuryl)-2-methyl-pyrazine is [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1,4-diketone and physiologically acceptable solvate thereof also.
7. each compound among the claim 1-6 that is used for the treatment of.
8. the compound that is used for the treatment of wherein among the claim 1-6 of illness that inhibition to the cGMP specific PDE has therapeutic value each.
9. each compound wherein has application in the medicine of illness of therapeutic value in preparation treatment among the claim 1-6 to the inhibition of cGMP specific PDE.
10. method that wherein inhibition of cGMP specific PDE is had the illness of therapeutic value for the treatment of people or non-human animal's body, this method comprise to each compound among the claim 1-6 of described human or animal body administering therapeutic significant quantity.
11. a pharmaceutical composition is comprising each compound and acceptable diluents or carrier among the claim 1-6.
12. comprise the preparation of drug combination method of each compound among the claim 1-6, this method comprises together mixes described compound with pharmaceutically acceptable diluent or carrier.
13. the method (A) of the compound of preparation claim 1, this method comprises uses primary amine R 1NH 2Processing formula (II) compound:
Figure A9619675100031
Wherein Alk represents C 1-6Alkyl, and Hal represents halogen atom; Or method (B), this method is included in catalyzer and exists down, in suitable solvent such as alcohol, and hydrogenation of formula (III) compound at elevated temperatures:
Figure A9619675100032
Wherein the definition of Alk is the same, and Cbz represents carbobenzoxy-(Cbz); Or method (C), this method comprises method (A) or (B), that continues also comprises:
I) mutual step of converting; And/or
Iii) solvate forms step.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104230960A (en) * 2013-06-06 2014-12-24 山东轩竹医药科技有限公司 Four-ring anaplastic lymphoma kinase inhibitor
CN104804016A (en) * 2014-01-23 2015-07-29 山东轩竹医药科技有限公司 Tetra-heterocyclic-fused anaplastic lymphoma kinase inhibitor
CN112041301A (en) * 2018-02-28 2020-12-04 费罗治疗公司 Compounds having iron death inducing activity and methods of use thereof

Families Citing this family (84)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6143746A (en) * 1994-01-21 2000-11-07 Icos Corporation Tetracyclic cyclic GMP-specific phosphodiesterase inhibitors, process of preparation and use
GB9401090D0 (en) * 1994-01-21 1994-03-16 Glaxo Lab Sa Chemical compounds
US6262059B1 (en) 1995-06-07 2001-07-17 Cell Pathways, Inc. Method of treating a patient having precancerous lesions with quinazoline derivatives
US5874440A (en) * 1995-06-07 1999-02-23 Cell Pathways, Inc. Method of treating a patient having precancerous lesions with phenyl pyrimidinone derivatives
US6200980B1 (en) 1995-06-07 2001-03-13 Cell Pathways, Inc. Method of treating a patient having precancerous lesions with phenyl purinone derivatives
US6232312B1 (en) 1995-06-07 2001-05-15 Cell Pathways, Inc. Method for treating patient having precancerous lesions with a combination of pyrimidopyrimidine derivatives and esters and amides of substituted indenyl acetic acides
US6060477A (en) * 1995-06-07 2000-05-09 Cell Pathways, Inc. Method of treating a patient having precancerous lesions with phenyl cycloamino pyrimidinone derivatives
US6046206A (en) * 1995-06-07 2000-04-04 Cell Pathways, Inc. Method of treating a patient having a precancerous lesions with amide quinazoline derivatives
GB9514473D0 (en) * 1995-07-14 1995-09-13 Glaxo Lab Sa Chemical compounds
US6331543B1 (en) 1996-11-01 2001-12-18 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use
JP2002505676A (en) 1997-06-23 2002-02-19 クイーンズ ユニバーシティー アット キングストン Microdose therapy
ES2137113B1 (en) 1997-07-29 2000-09-16 Almirall Prodesfarma Sa NEW DERIVATIVES OF TRIAZOLO-PIRIDAZINAS HETEROCICLICOS.
US5852035A (en) * 1997-12-12 1998-12-22 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure to substituted N- arylmethyl and heterocyclmethyl-1H-pyrazolo (3,4-B) quinolin-4-amines
US6410584B1 (en) 1998-01-14 2002-06-25 Cell Pathways, Inc. Method for inhibiting neoplastic cells with indole derivatives
US6046199A (en) * 1998-01-14 2000-04-04 Cell Pathways, Inc. Method of inhibiting neoplastic cells with tetracyclic pyrido[3,4-B]indole derivatives
US5942520A (en) * 1998-01-27 1999-08-24 Cell Pathways, Inc. Method for inhibiting neoplastic cells by exposure to substituted N-cycloalkylmethyl-1-H-pyrazolo (3,4-B) quinolone-4 amines
US5990117A (en) * 1998-04-15 1999-11-23 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure to quinazoline derivatives
US6124303A (en) * 1998-09-11 2000-09-26 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure to 9-substituted 2-(2-N-aloxyphenyl) purin-6-ones
US6268372B1 (en) 1998-09-11 2001-07-31 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure to 2,9-disubstituted purin-6-ones
US6326379B1 (en) 1998-09-16 2001-12-04 Bristol-Myers Squibb Co. Fused pyridine inhibitors of cGMP phosphodiesterase
US6200771B1 (en) 1998-10-15 2001-03-13 Cell Pathways, Inc. Method of using a novel phosphodiesterase in pharmaceutical screeing to identify compounds for treatment of neoplasia
US6133271A (en) * 1998-11-19 2000-10-17 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure thienopyrimidine derivatives
US6187779B1 (en) 1998-11-20 2001-02-13 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure to 2,8-disubstituted quinazoline derivatives
US6369092B1 (en) 1998-11-23 2002-04-09 Cell Pathways, Inc. Method for treating neoplasia by exposure to substituted benzimidazole derivatives
US6077842A (en) * 1998-11-24 2000-06-20 Cell Pathways, Inc. Method of inhibiting neoplastic cells with pyrazolopyridylpyridazinone derivatives
US6486155B1 (en) 1998-11-24 2002-11-26 Cell Pathways Inc Method of inhibiting neoplastic cells with isoquinoline derivatives
US6034099A (en) * 1998-11-24 2000-03-07 Cell Pathways, Inc. Method for inhibiting neoplastic lesions by administering 4-(arylmethylene)- 2, 3- dihydro-pyrazol-3-ones
US6020379A (en) * 1999-02-19 2000-02-01 Cell Pathways, Inc. Position 7 substituted indenyl-3-acetic acid derivatives and amides thereof for the treatment of neoplasia
NO20002097L (en) 1999-04-30 2001-10-26 Lilly Icos Llc Preparation items
US6613768B1 (en) 1999-04-30 2003-09-02 Lilly Icos Llc Treatment of female arousal disorder
US6451807B1 (en) 1999-04-30 2002-09-17 Lilly Icos, Llc. Methods of treating sexual dysfunction in an individual suffering from a retinal disease, class 1 congestive heart failure, or myocardial infarction using a PDE5 inhibitor
US7182958B1 (en) * 1999-08-03 2007-02-27 Lilly Icos Llc. β-carboline pharmaceutical compositions
US20040152106A1 (en) * 1999-10-07 2004-08-05 Robertson Harold A. Gene necessary for striatal function, uses thereof, and compounds for modulating same
WO2001024781A2 (en) * 1999-10-07 2001-04-12 Novaneuron Inc. Gene necessary for striatal function, uses thereof, and compounds for modulating same
DZ3218A1 (en) 1999-10-11 2001-04-19 Pfizer PYRIMIDINE-7-ONES 5- (2-SUBSTITUTEES-5-HETEROCYCLYLSULPHONYLPYRIDE-3-YL) -DIHYDROPYRAZOLO [4,3-D] AS PHOSPHODIESTERASE INHIBITORS
US20050020547A1 (en) * 1999-11-08 2005-01-27 Pfizer Inc. Compounds for the treatment of female sexual dysfunction
IL139456A0 (en) 1999-11-08 2001-11-25 Pfizer Compounds for the treatment of female sexual dysfunction
US6569638B1 (en) 2000-03-03 2003-05-27 Cell Pathways, Inc Method for screening compounds for the treatment of neoplasia
CN1436080A (en) 2000-04-19 2003-08-13 利利艾科斯有限公司 Use of cyclic-GMP-specific phosphodiesterase inhibitor for treating parkinson's disease
CA2406947A1 (en) * 2000-04-19 2001-10-25 Johns Hopkins University Methods for prevention and treatment of gastrointestinal disorders
MXPA02012470A (en) 2000-06-23 2004-01-26 Lilly Icos Llc Cyclic gmp-specific phosphodiesterase inhibitors.
US7034027B2 (en) * 2000-08-02 2006-04-25 Lilly Icos Llc Fused heterocyclic derivatives as phosphodiesterase inhibitors
US6503894B1 (en) 2000-08-30 2003-01-07 Unimed Pharmaceuticals, Inc. Pharmaceutical composition and method for treating hypogonadism
AU8444401A (en) * 2000-09-06 2002-03-22 Tanabe Seiyaku Co Preparations for oral administration
US6821978B2 (en) * 2000-09-19 2004-11-23 Schering Corporation Xanthine phosphodiesterase V inhibitors
CA2423308A1 (en) 2000-10-02 2002-04-11 Lilly Icos Llc Condensed pyridoindole derivatives
EP1325007B1 (en) * 2000-10-02 2005-06-15 Lilly Icos LLC Hexahydropyrazino[1'2':1,6]-pyrido[3,4-b]indole-1,4-dione derivatives for the treatment of cardiovascular disorders and erectile disfunction
MXPA03003971A (en) 2000-11-06 2004-02-12 Lilly Icos Llc Indole derivatives as pde5-inhibitors.
MXPA03004023A (en) * 2000-11-08 2004-02-12 Lilly Icos Llc Condensed pyrazindione derivatives as pde inhibitors.
AU2002230217B2 (en) * 2001-02-15 2005-02-17 Tanabe Seiyaku Co., Ltd. Tablets quickly disintegrated in oral cavity
DE10118305A1 (en) * 2001-04-12 2002-10-17 Bayer Ag Composition for intranasal administration of cGMP PDE inhibitor for treatment of erectile dysfunction, also containing local anesthetic to prevent nasal blockage and improve absorption
DE10118306A1 (en) 2001-04-12 2002-10-17 Bayer Ag Composition for intranasal administration of imidazo-triazinone derivative cGMP PDE inhibitor for treatment of erectile dysfunction, also containing local anesthetic to prevent nasal blockage and improve absorption
EP1401449B1 (en) * 2001-06-05 2007-04-25 Lilly Icos LLC Tetracyclic compounds as pde5-inhibitors
ATE335742T1 (en) 2001-06-21 2006-09-15 Lilly Icos Llc CARBOLINE DERIVATIVES AS PDEV INHIBITORS
JP2005509038A (en) 2001-11-09 2005-04-07 シェーリング　コーポレイション Polycyclic guanine derivative phosphodiesterase V inhibitor
WO2003053923A2 (en) 2001-12-20 2003-07-03 Applied Research Systems Ars Holding N.V. Pyrrolidine derivatives as prostaglandin modulators
US7276529B2 (en) 2002-03-20 2007-10-02 Celgene Corporation Methods of the treatment or prevention of exercise-induced asthma using (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione
US6962940B2 (en) 2002-03-20 2005-11-08 Celgene Corporation (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione: methods of using and compositions thereof
US7208516B2 (en) 2002-03-20 2007-04-24 Celgene Corporation Methods of the treatment of psoriatic arthritis using (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione
US7893101B2 (en) 2002-03-20 2011-02-22 Celgene Corporation Solid forms comprising (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, compositions thereof, and uses thereof
EA008666B1 (en) * 2002-07-31 2007-06-29 ЛИЛЛИ АЙКОС эЛ-эЛ-Си Modified pictet-spengler reaction and products prepared therefrom
EP2526958B1 (en) * 2003-06-13 2017-10-18 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
US8063214B2 (en) * 2004-10-28 2011-11-22 Dr. Reddy's Laboratories Limited Polymorphic forms of tadalafil
US8506934B2 (en) 2005-04-29 2013-08-13 Robert I. Henkin Methods for detection of biological substances
EP2275095A3 (en) 2005-08-26 2011-08-17 Braincells, Inc. Neurogenesis by muscarinic receptor modulation
EP2258359A3 (en) 2005-08-26 2011-04-06 Braincells, Inc. Neurogenesis by muscarinic receptor modulation with sabcomelin
EP2377530A3 (en) 2005-10-21 2012-06-20 Braincells, Inc. Modulation of neurogenesis by PDE inhibition
EP2314289A1 (en) 2005-10-31 2011-04-27 Braincells, Inc. Gaba receptor mediated modulation of neurogenesis
ZA200804550B (en) 2005-11-09 2009-08-26 Combinatorx Inc Methods, compositions, and kits for the treatment of medical conditions
US20100216734A1 (en) 2006-03-08 2010-08-26 Braincells, Inc. Modulation of neurogenesis by nootropic agents
CA2651813A1 (en) 2006-05-09 2007-11-22 Braincells, Inc. Neurogenesis by modulating angiotensin
WO2007134077A2 (en) 2006-05-09 2007-11-22 Braincells, Inc. 5 ht receptor mediated neurogenesis
AU2007292848A1 (en) * 2006-09-08 2008-03-13 Braincells, Inc. Combinations containing a 4-acylaminopyridine derivative
US20100184806A1 (en) 2006-09-19 2010-07-22 Braincells, Inc. Modulation of neurogenesis by ppar agents
WO2008095136A2 (en) 2007-01-31 2008-08-07 Henkin Robert I Methods for detection of biological substances
US8580801B2 (en) 2008-07-23 2013-11-12 Robert I. Henkin Phosphodiesterase inhibitor treatment
US20100216805A1 (en) 2009-02-25 2010-08-26 Braincells, Inc. Modulation of neurogenesis using d-cycloserine combinations
EP2804603A1 (en) 2012-01-10 2014-11-26 President and Fellows of Harvard College Beta-cell replication promoting compounds and methods of their use
WO2014055801A1 (en) 2012-10-05 2014-04-10 Henkin Robert I Phosphodiesterase inhibitors for treating taste and smell disorders
WO2015089105A1 (en) 2013-12-09 2015-06-18 Respira Therapeutics, Inc. Pde5 inhibitor powder formulations and methods relating thereto
WO2015126944A1 (en) 2014-02-18 2015-08-27 Henkin Robert I Methods and compositions for diagnosing and treating loss and/or distortion of taste or smell
US10300042B2 (en) 2014-06-23 2019-05-28 Celgene Corporation Apremilast for the treatment of a liver disease or a liver function abnormality
US11234977B2 (en) 2017-12-20 2022-02-01 Novartis Ag Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals
US11040964B2 (en) 2019-02-27 2021-06-22 Ferro Therapeutics, Inc. Compounds and methods of use

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3644384A (en) * 1969-06-09 1972-02-22 Sterling Drug Inc Certain 2-(alpha-haloacetyl) - 1 2 3 4-tetrahydro - 9h - pyrido(3 4-b)indole-3-carboxylates and derivatives
US3717638A (en) * 1971-03-11 1973-02-20 Sterling Drug Inc 1,2,3,4,6,7,12,12A-OCTAHYDRO-2-PHENYLPYRAZINO[2',1':6,1]PYRIDO[3,4-b]INDOLES AND INTERMEDIATES THEREFOR
US3917599A (en) * 1973-03-30 1975-11-04 Council Scient Ind Res 2-Substituted-1,2,3,4,6,7,12,12A-octahydropyrazino(2{40 ,1{40 :6,1)pyrido(3,4-B)indoles
GB1454171A (en) * 1973-10-19 1976-10-27 Council Scient Ind Res Tetracyclic compounds
US4188390A (en) * 1977-11-05 1980-02-12 Pfizer Inc. Antihypertensive 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl) piperazin-1-yl or homopiperazin-1-yl]quinazolines
US4656174A (en) * 1982-07-24 1987-04-07 Pfizer Inc. Quinoline therapeutic agents
IT1217190B (en) * 1988-04-22 1990-03-14 Recordati Chem Pharm USEFUL COMPOUNDS FOR THE TREATMENT AND DIAGNOSIS OF HURRY DYSFUNCTIONS
EP0357122A3 (en) * 1988-08-29 1991-10-23 Duphar International Research B.V Use of beta-carbolines, their bio-isosteric benzofuran and benzothiophene analogues for the manufacture of a medicament having cytostatic properties
DE3830096A1 (en) * 1988-09-03 1990-03-15 Hoechst Ag PIPERAZINDIONE WITH PSYCHOTROPER EFFECT
FR2649613B1 (en) * 1989-07-11 1991-09-27 Virag Ronald VASO-ACTIVE MEDICINE
JPH0344324A (en) * 1989-07-13 1991-02-26 Kazuoki Tsuchiya Sexual function invigorator
US5270323A (en) * 1990-05-31 1993-12-14 Pfizer Inc. Method of treating impotence
EP0459666B1 (en) * 1990-05-31 1994-11-09 Pfizer Inc. Medicaments against impotence
GB9013750D0 (en) * 1990-06-20 1990-08-08 Pfizer Ltd Therapeutic agents
GB9114760D0 (en) * 1991-07-09 1991-08-28 Pfizer Ltd Therapeutic agents
GB9218322D0 (en) * 1992-08-28 1992-10-14 Pfizer Ltd Therapeutic agents
GB9311920D0 (en) * 1993-06-09 1993-07-28 Pfizer Ltd Therapeutic agents
GB9401090D0 (en) * 1994-01-21 1994-03-16 Glaxo Lab Sa Chemical compounds

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104230960A (en) * 2013-06-06 2014-12-24 山东轩竹医药科技有限公司 Four-ring anaplastic lymphoma kinase inhibitor
CN104230960B (en) * 2013-06-06 2017-02-15 山东轩竹医药科技有限公司 Four-ring anaplastic lymphoma kinase inhibitor
CN104804016A (en) * 2014-01-23 2015-07-29 山东轩竹医药科技有限公司 Tetra-heterocyclic-fused anaplastic lymphoma kinase inhibitor
CN104804016B (en) * 2014-01-23 2017-06-20 山东轩竹医药科技有限公司 Four and ring class anaplastic lymphoma kinase inhibitor
CN112041301A (en) * 2018-02-28 2020-12-04 费罗治疗公司 Compounds having iron death inducing activity and methods of use thereof

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AR003455A1 (en) 1998-08-05
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CO4700455A1 (en) 1998-12-29
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ZA965934B (en) 1997-02-03
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